JPH09110819A - N-(4-bromo-2-fluorobenzyl) carbamate and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new N-(4-bromo-2-fluorobenzyl) carbamate important in a synthesis of a new aldose-reductase inhibitor.

SOLUTION: This new N-(4-bromo-2-fluorobenzyl) carbamate is expressed by the formula (R is a 1-12C alkyl, etc.) and ortho-benzyl N-(4-bromo-2- fluorobenzyl) carbamate is exemplified. The compound of the formula is obtained by reacting 4-bromo-2-fluorobenzyl halide with an alkali metal cyanate, etc., in a dipolar aprotic solvent in the presence of an alcohol (ROH).

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to N- (4-bromo-2-
Fluorobenzyl) carbamate and a method for producing the same.

[0002]

New N- (4-bromo-2-fluorobenzyl) carbamates are starting materials for nitrogen-containing heterocycles, pharmaceutical intermediates and crop protection agents. Compounds of this type are particularly suitable for the novel aldose-reductase inhibitors (a
ldose-reductase inhibitor) (K. Ogawva, I. Yamawak
i, YI Matsusita, N. Nomura, PF Kador, JH
Kinoshita, Eur. J. Med. Chem. 28, 769, (1993)).

International patent application specification WO 94 10 132A1
Substituted benzyl carbamates having herbicidal properties are disclosed. Japanese Patent Publication No. 45-3770 [CA 72: 1323
44m (1970)], the synthesis of N-benzyl carbamate is reported.

[0004]

It is therefore desirable to provide new compounds of this type of substance in order to expand the scope of the synthesis of known products on the one hand and to produce new products on the other hand. Was there.

[0005]

This problem is solved by the following general formula I

[0006]

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Where R is (C ₁ -C ₁₂ ) -alkyl, benzyl or phenyl, where the benzyl and phenyl groups are (C ₁ -C ₃ ) alkyl or (C ₁ -C ₃ ). N- (4-bromo-2-fluorobenzyl) carbamate represented by (optionally substituted by alkoxy).

Preferred compounds have the general formula I
Is a (C ₁ -C ₄ ) alkyl, benzyl or methoxybenzyl compound. The key compound is O-benzyl N- (4
-Bromo-2-fluorobenzyl) carbamate, O-methyl N- (4-bromo-2-fluorobenzyl) carbamate,
O-ethyl N- (4-bromo-2-fluorobenzyl) carbamate, Op-methoxybenzyl N- (4-bromo-2-fluorobenzyl) carbamate, O-butyl N- (4-bromo-2-fluorobenzyl) It is a carbamate.

The present invention further provides a process for the preparation of compounds of general formula I, wherein 4-bromo-2-fluorobenzyl halide and an alkali metal cyanate or ammonium cyanate are used in a dipolar aprotic solvent. solven
t) in the presence of the alcohol ROH. 4-Bromo-2-fluorobenzyl bromide, potassium cyanate and DM as solvent
Using F, the temperature is 30 to 150 ° C., preferably 80 to
It is useful to carry out at 140 ° C, especially 100-120 ° C.

The reaction is generally complete in 1 to 3 hours. It is advantageous to use an excess of cyanate and alcohol, especially with respect to 1 mol of benzyl halide,
It is advantageous to use 1.1 to 3 mol of cyanate and 1.1 to 4 mol of alcohol.

[0011]

The present invention is further illustrated by the following examples, but the invention is not limited thereto. Example 1 Synthesis of O-benzyl N- (4-bromo-2-fluorobenzyl) carbamate Anhydrous, amine-free DMF (180 mL) and benzyl alcohol (28 mL) and KOCN (0.247 mol, 20
g) in 500 mL equipped with reflux condenser and drying tube
Into a 2-neck round bottom flask. A solution of 4-bromo-2-fluorobenzyl bromide (0.075 mol, 20 g) in DMF (20 mL) is added rapidly (in 1 min) from a dropping funnel while stirring the reaction mixture at room temperature. The resulting suspension is then heated with stirring to about 110 ° C. and further stirred at this temperature for about 1.5 hours. Then the mixture is cooled to room temperature. The salts present in the reaction mixture are suction filtered through a frit. The solvent and excess benzyl alcohol are removed from the vacuum filtrate. The light yellow oily residue crystallizes on cooling with ice. The bright crystalline mass obtained is washed with water, filtered and dried. Yield: 23.2 g (91.5% of theory). p. : 82-84 ° C GC / MS: M ⁺ = 337, KBr IR [cm ^-1 ]: 3342 (m) NH, 1689
(s) C = O, 1535 (m) NH-C, 1276 (m) COC Example 2 Synthesis of O-methyl N- (4-bromo-2-fluorobenzyl) carbamate Anhydrous, amine-free DMF (500 mL) and methanol (50 mL) and KOCN (0.62 mol, 50 g) are introduced into a 1000 mL 2-neck round bottom flask equipped with a reflux condenser and drying tube. A solution of 4-bromo-2-fluorobenzyl bromide (0.186 mol, 50 g) in DMF (50 mL) is added rapidly via a dropping funnel while stirring the reaction mixture at room temperature. The resulting suspension is then heated with stirring to about 100 ° C. and stirred at this temperature for about 1.5 hours. Then the mixture is cooled to room temperature. The salts present in the reaction mixture are suction filtered through a frit. The solvent and excess methanol are removed from the vacuum filtrate. The oily residue is cooled and crystallized. The bright crystalline mass obtained is washed with water, filtered and dried. Yield: 44.3 g (91% of theory). p. : 66-67.5 ° C GC / MS: M ⁺ = 261, KBr IR [cm ^-1 ]: 3338 (m) NH, 1694
(s) C = O, 1536 (m) NH-C, 1280 (m) COC Further, O-organyl N- (4-bromo-2-fluorobenzyl) carbamate was prepared in the same manner as in Example 1.

Claims (9)

[Claims] [Claim 1] The following general formula I Where R is (C ₁ -C ₁₂ ) -alkyl, benzyl or phenyl, where the benzyl and phenyl groups are (C
₁ -C ₃₎ alkyl or _{(C 1 -C 3) N- (} 4- bromo-2-fluorobenzyl) carbamate represented by may also be) optionally substituted by alkoxy. 2. The compound according to claim 1, wherein in the general formula I, R ₁ is (C ₁ -C ₄ ) alkyl, benzyl or methoxybenzyl. 3. A compound of general formula I is O-benzyl N- (4-
Bromo-2-fluorobenzyl) carbamate, O-methyl
N- (4-Bromo-2-fluorobenzyl) carbamate, O-
Ethyl N- (4-bromo-2-fluorobenzyl) carbamate, Op-methoxybenzyl N- (4-bromo-2-fluorobenzyl) carbamate or O-butyl N- (4-bromo-2-
The compound according to claim 1, which is fluorobenzyl) carbamate. 4. A general formula characterized by reacting 4-bromo-2-fluorobenzyl halide with an alkali metal cyanate or ammonium cyanate in a dipolar aprotic solvent in the presence of alcohol ROH. Process for producing compounds of I. 5. The method according to claim 4, wherein the 4-bromo-2-fluorobenzyl halide used is bromide. 6. The method according to claim 4, wherein the cyanate salt used is potassium cyanate. 7. The method according to claim 4, wherein the solvent used is DMF. 8. The reaction is carried out at 30 to 150 ° C., preferably 8
Process according to any of claims 4 to 7, carried out at 0 to 140 ° C, especially 100 to 120 ° C. 9. For 1 mol of benzyl halide, 1.
9. A method according to any of claims 4 to 8 using 1 to 3 mol of cyanate and 1.1 to 4 mol of alcohol.